Autism and cerebellar dysfunction: Evidence from animal models

Tsai, Peter T.

doi:10.1016/j.siny.2016.04.009

Cited by 34 publications

(32 citation statements)

References 75 publications

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“…The social deficits observed in our cerebellar-specific manipulation are consistent with the considerable evidence for the cerebellum's involvement in social behavior, e.g. in the context of ASD and cerebellar cognitive affective syndrome (Schmahmann, 2019;Tsai, 2016;Wang et al, 2014). What sets our findings apart from previous cerebellar-specific manipulations is that the social deficits were observed exclusively in female mice.…”

Section: Sex-specific Effects On Sociability In Cb  Ko Micesupporting

confidence: 86%

“…As Average responses to the CS alone and to paired CS + US stimulation were very similar for control and cb  KO mice on days 5 and 15 (Figure 3 L, N). Since cerebellar deficits can affect motor learning (Kloth et al, 2015;Tsai, 2016) we also performed a 3-day accelerating rotarod paradigm. We found that there was no difference between control mice and cb  KO mice in initial performance on the rotarod (control, 90  5 s on rotarod, n=36, cb  KO, 89  8 s on rotarod, n=20, p>0.9, Mann-Whitney test; Figure Thus, remarkably, despite hyperexcitability of the cerebellar input layer in cb  KO mice, we did not detect any gait abnormalities or defects in motor learning.…”

Section: Resultsmentioning

confidence: 99%

“…Our findings indicate that loss of GABA A in cerebellar GCs contributes to increased anxiety-like behavior that could affect sociability. Second, cerebellar dysfunction can lead to social deficits in humans and in animal models (Badura et al, 2018;Carta et al, 2019;Schmahmann and Sherman, 1998;Tsai, 2016).…”

Section: Resultsmentioning

confidence: 99%

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Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Rudolph

Guo

Pashkovski

et al. 2019

Preprint

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GABAA receptors containing the GABAA subunit (GABAARs) are involved in many physiological and pathophysiological processes, such as sleep, pain, stress, anxiety-related behaviors, and postpartum depression. These extrasynaptically located, high affinity and slowly desensitizing receptors mediate tonic inhibition throughout the brain, including in granule cells (GCs) of the cerebellar input layer. However, the extent to which GABAARs control the excitability of the cerebellar input layer and ultimately regulate behavior is unknown.We therefore deleted GABAA subunits specifically from GCs and determined the behavioral consequences in mice. Deletion reduced tonic inhibition and increased input layer excitability, but remarkably, did not affect either locomotion or motor learning. Unexpectedly, GABAA deletion heightened anxiety-like behaviors, and caused female-specific alterations in social and maternal behavior. Our findings establish that the cerebellar input layer is critical for regulating diverse behaviors that are relevant to psychiatric and neurodevelopmental disorders but were previously not associated with the cerebellum.

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Section: Sex-specific Effects On Sociability In Cb  Ko Micesupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

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Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Rudolph

Guo

Pashkovski

et al. 2019

Preprint

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“…ASDs are often associated with mutations in genes coding for synaptic proteins (Qiu et al, 2012;Banerjee et al, 2014;De Ru-beis and Buxbaum, 2015;Kim et al, 2016) bringing about neurotransmission abnormalities (Curatolo et al, 2014;Ellegood et al, 2015;Kloth et al, 2015;Mercer et al, 2016;Sztainberg and Zoghbi, 2016;Tsai, 2016;Tu et al, 2017). The consequent microcircuit alterations have mainly been analyzed in the neocortex revealing the following: (1) hyper-reactivity to stimulation, accompanied by altered neuronal excitability and synaptic plasticity, was related to increased glutamatergic transmission (Rinaldi et al, 2007(Rinaldi et al, , 2008bMarkram et al, 2008;Markram and Markram, 2010); (2) dysregulation of the excitation (E)/inhibition (I) balance was related to various alterations at excitatory and inhibitory synapses (Rubenstein and Merzenich, 2003;Gogolla et al, 2009;Uzunova et al, 2016); and (3) altered modular organization of microcircuits (Casanova, 2003(Casanova, , 2006Hutsler and Casanova, 2016) was related to reduced lateral inhibition, bringing about changes in the spatial organization of neuronal activation and synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

Soda

Mapelli²,

Locatelli³

et al. 2019

J. Neurosci.

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Autism spectrum disorders (ASDs) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASDs has been suggested, but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 (Islet Brain-2) KO mice of either sex. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan-McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition. IB2 KO granule cells showed a larger NMDA receptor-mediated current and enhanced intrinsic excitability, raising the excitatory/inhibitory balance. Furthermore, the spatial organization of granular layer responses to mossy fibers shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core and weaker inhibition in the surround. Finally, the size and extension of long-term synaptic plasticity were remarkably increased. These results show for the first time that hyperexcitability and hyperplasticity disrupt signal transfer in the granular layer of IB2 KO mice, supporting cerebellar involvement in the pathogenesis of ASD. This article shows for the first time a complex set of alterations in the cerebellum granular layer of a mouse model [IB2 (Islet Brain-2) KO] of autism spectrum disorders. The IB2 KO in mice mimics the deletion of the corresponding gene in the Phelan-McDermid syndrome in humans. The changes reported here are centered on NMDA receptor hyperactivity, hyperplasticity, and hyperexcitability. These, in turn, increase the excitatory/inhibitory balance and alter the shape of center/surround structures that emerge in the granular layer in response to mossy fiber activity. These results support recent theories suggesting the involvement of cerebellum in autism spectrum disorders.

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“…The review of neuroimaging studies by Anagnostou and Taylor published in 2011 states that great heterogeneity exists within ASD and points to underlying neuroanatomical atypicalities in connectivity [13]. The topic of abnormal connectivity is being further developed in research regarding cerebellar involvement in repetitive, stereotypical behaviors [14]. For example, many genes connected to ASD susceptibility also play important role in cerebellar development [15].…”

Section: Neuroimaging and Eegmentioning

confidence: 99%

The assessment of neuropsychological functioning in adults with autism spectrum disorders – tackling the challenge

Wojciechowska¹,

Walęcka²,

Wichniak³

2019

Arch Psych Psych

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Assessment of neuropsychological functioning in adults with ASD has been researched for a while now, yet there seems to be no consensus on what the actual profile of impairment in this group of patients is. Conflicting results of various studies may be connected to many factors: heterogeneity of the clinical group, changes in diagnostic criteria, applied tests and assessment methods, trouble with matching healthy controls because of individual differences in neuropsychological functioning. The aim of the following paper is to analyse the selected domains of cognitive functioning in adult ASD individuals. It seems that the most consistent findings in this group are connected to central coherence and cognitive flexibility which in turn affect social functions and repetitive behavioral patterns-two core issues of ASD patients. The implications of those findings for clinical practice and diagnostic approach to adult ASD patients are discussed. Especially in regards to high-functioning ASD individuals whose neuropsychological impairment may not show in a neuropsychological assessment.

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Autism and cerebellar dysfunction: Evidence from animal models

Cited by 34 publications

References 75 publications

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

The assessment of neuropsychological functioning in adults with autism spectrum disorders – tackling the challenge

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Autism and cerebellar dysfunction: Evidence from animal models

Cited by 34 publications

References 75 publications

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

The assessment of neuropsychological functioning in adults with autism spectrum disorders – tackling the challenge

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Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

Cerebellum-specific deletion of the GABA_Areceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance